sparteine i-PrLi, Et Asymmetric Deprotonation · Cox and Simpkins, "Asymmetric Synthesis Using Homochiral Lithium Amide Bases," Tetrahedron: Asymmetry, 1991, 2 (1), 1-26. 8. Eames,

Asymmetric Deprotonation

Fe

O

Fe

O

N(i-Pr)2

1. n-BuLi (–)-sparteine Et2O, -78°C

2. Ph2PCl

PPh2

N(i-Pr)2 90% ee

David Ebner

Stoltz Group Literature Presentation

March 28, 2005

N

Ph

Li

CF3NO

t-Bu

OTMS

t-Bu

TMSCl, HMPATHF, -100°C

93% ee

Ligands, Bases, and Applications

O

OHH

H

84% ee(–)-sparteine

i-PrLi, Et2O, -98°C

Enantioselective Deprotonation

Reaction Pathways

R R'

Ha Hb base

- Ha

- Hb

R R'

M Hb

R R'

Ha M

electrophile

electrophile

R R'

E Hbretention

inversion

retention

inversion

R R'

Hb E

R R'

Ha E

R R'

E Ha

possibleanion

inversion


Reaction Pathways

R R'

Ha Hb base

- Ha

- Hb

R R'

M Hb

R R'

Ha M

electrophile

electrophile

R R'

E Hbretention

inversion

retention

inversion

R R'

Hb E

R R'

Ha E

R R'

E Ha

possibleanion

inversion


What Will NOT Be Covered

R R'

Ha Hb base

- Ha

- Hb

R R'

M Hb

R R'

Ha M

electrophile

electrophile

R R'

E Hbretention

inversion

retention

inversion

R R'

Hb E

R R'

Ha E

R R'

E Ha

possibleanion

inversion

Great Chemistry Not Covered Today:- Chiral Auxiliary-Directed Deprotonation- Enantioselective Additions of Achiral Anions to Chiral or Homochiral Electrophiles • Aldols • Carbolithiations • Achiral Alkyllithium Additions to Electrophiles- Enantioselective Reactions of Racemic or Equilibrating Anions • Deprotonation Adjacent to S, P, Se, Ph (usually) • Wittig Rearrangements


Outline and Key Players

I. meso-Ketone Deprotonations

II. meso-Epoxide Deprotonations

a. -Deprotonation

b. -Deprotonation

III. Deprotonation Adjacent to Heteroatoms

a. O: Alkyl and Allylic Systems

b. N: Alkyl, Benzylic, and Allylic Systems

IV. Other Enantioselective Deprotonations

a. Elimination of HX

b. Aromatic Lithiation

General Reviews:

1. Majewski, "Enantioselective Deprotonation of Cyclic Ketones," in Advances in Asymmetric Synthesis, Vol. 3, pp 39-76, JAI Press, London:

1998.

2. Waldmann, "Enantioselective Deprotonation and Protonation," in Organic Synthesis Highlights II, H. Waldmann, ed. pp 19-28, VCH, Weinheim:

1995.

3. Organolithiums in Enantioselective Synthesis, D. Hodgson, ed. Springer, New York: 2003. (Whole book is good, especially pp 61-286.)

4. O'Brien, "Recent Advances in Asymmetric Synthesis Using Chiral Lithium Amide Bases," J. Chem. Soc., Perkin Trans. 1, 1998, 1439-1457.

5. Hoppe and Hense, "Enantioselective Synthesis with Lithium/(–)-Sparteine Carbanion Pairs," Angew. Chem. Int. Ed. Engl. 1997, 36, 2282-2313.

6. Hodgson, Gibbs, and Lee, "Enantioselective Desymmetrisation of Achiral Epoxides," Tetrahedron, 1996, 52 (46), 14361-14384.

7. Cox and Simpkins, "Asymmetric Synthesis Using Homochiral Lithium Amide Bases," Tetrahedron: Asymmetry, 1991, 2 (1), 1-26.

8. Eames, "Recent Developments in Enantioselective Deprotonation Mediated by Sub-Stoichiometric Quantities of Chiral Bases," Eur. J. Org.

Chem., 2002, 393-401.

9. Beak, Basu, Gallagher, Park and Thayumanavan, "Regioselective, Diastereoselective, and Enantioselective Lithiation-Substitution Sequences:

Reaction Pathways and Synthetic Applicaitons," Acc. Chem. Res. 1996, 29, 552-560.

K. Koga

Tokyo

Ketones

N. Simpkins

Nottingham

Ketones and Aromatics

M. Majewski

Saskatchewan

Ketones

D. Hodgson

Oxford

Epoxides

D. Hoppe

Muenster

Heteroatoms: O

P. Beak

Illinois, Urbana-Champaign

Heteroatoms: N

R

O

R

O

HH

ProtonsDifferentiatedby Chiral Base

H H Li-amideBase

(Additives)

R

O

HH

LiLn

NR'R''

R

O

H

LnLi

NH

R'

R''

E+

R

OE

H

OR

R

O

H E

Asymmetric Deprotonation of meso Cyclic Ketones

General Considerations

O

HHR Li-amide

Base

(Additives)?

Chiral Lithium Amides Used in Ketone Deprotonations

Only a Few of the Many!

Ph N

Li

Ph Ph N

Li

Me

N

Li

Me

Ph N

Li

CF3

H

NPh

LiN

Ph

N

Ph

Li LiPh Ph

N

Ph

Li

t-Bu

N

Ph

Li

CF3

H

NPh

Li

N

Ph

Li

N

N

N

N

H

N

Li

Ph

N

Li

Ph

N

N

Li

NLi

NN

Li

Ph Ph

NPh

Li

Prochiral 4-Substituted Cyclohexanones

Enantioselective Deprotonation of Simple Substrates

Ph N

Li

PhN

Ph

Li

CF3N

O

R

OTMS

R

Li-amideTMSCl

HMPATHF, -100°C

% Yield % eeR

Me

i-Pr

t-Bu

Ph

76 94

92 95

95 93

88 93

O

t-Bu

OTMS

t-Bu

Li-amideTMSCl

THF

Temp (°C) Quench % eeLiCl (equiv)

-78

-90

-78

-78

Internal

Internal

External

External

0

0

0

0.5

69

88

23

83

Koga, et. al. Tetrahedron 1997, 53, 13641 Simpkins, et. al. J. Chem. Soc., Perkin Trans. 1 1993, 3113

Tropinone Derivatives

Different Conditions and Electrophiles Lead to a Variety of Products

Majewski, et. al. Tetrahedron Lett. 1994, 35, 3653 Tetrahedron Lett. 1995, 36, 5465

N

O

NN

Ph

Li

t-Bu

LiCl, THF, -78°C

N

OLi95% ee

N

OHOH

Ph

PhCHO MeO2CCNN

OMeO2C H

ClCO2Bn

O

N

BnO2C

Other Prochiral Cyclic Substrates

Similar Ligands Yield Good ee's with a Variety of Electrophiles

Ph N

Li

Ph

O

OTMS84% ee

60% ee

O O

t-Bu

OOHH

OTMSBnO

96%84% ee

OTMSPh

81%71% ee

N

Li

OTMSTBSO

90%90% ee

OTMSn

n = 3: >99% een = 5: 95% ee

N

Li

t-Bu

Ph

N

N

OTMS

62%85% ee

O

O

97% ee

CO2MeOTESPh

67%92% ee

Ph N

H

H

OTMSO

O

95%83% ee

N OO

Ph

TMSH

72%91% ee

Catalytic Asymmetric Ketone Deprotonations

Early Efforts Lead to Moderate Selectivity

Koga, et. al. Tetrahedron 1997, 53, 1698

O

R

OTMS

R

1. Base, THF, -78°C HMPA (2.4 equiv)

2. TMSCl

N

Ph

Li

CF3N

% Yield % eeR

Me

i-Pr

t-Bu

Ph

78

75 79

77 80

85 81

NN N

Li

1.2 equiv

2.4 equiv

0.3 equiv

1.5 equiv DABCO

% Yield % ee

70 75

80 76

77 76

83 79

N

Ph

H

CF3N

Stoichiometric, 1 h Catalytic, 1.5 h

82

Chiral Magnesium Amides in Ketone Deprotonation

Less Reactive Alternative to Lithium Amides

Ph N Ph2

Mg

O

R

HMPA (0.5 equiv), TMSClTHF, -78°C, 6 h

OTMS

R

% Conv. % eeR

Me

i-Pr

t-Bu

Ph

81 82

77 90

79 74

82 82

n-Pr 88 76

O

i-Pri-Pr Ph N Ph2

Mg

HMPA (0.5 equiv)TMSCl, THF

OTMS

i-Pri-Pr

Temp (°C) Time (h) % ee% Conv.

-78

-60

-40

rt

39

6

6

2

54

66

99

100

>99

99.4

98.8

82

i-Pr i-Pr

O

(±)-

i-Pr i-Pr

OTMS

i-Pr i-Pr

O

+Ph N Ph

2Mg

HMPA (0.5 equiv), TMSClTHF, -40°C, 67 h

66%, 62% ee 34%, 88% ee

Kerr, Henderson, et. al. Tetrahedron, 2002, 58, 4573

Deprotonation of Epoxides

Early Surprising Results

OLiNEt2

Et2O,

H

H

OH

OHCHO + +

55-60% 10-15%32%

Cope, et. al. J. Am. Chem. Soc. 1958, 80, 2849

OOLiNEt2

Et2O, -10°C

95% Cope and Tiffany, J. Am. Chem. Soc. 1951, 73, 4158

H

H

OH

HB:

H

H

OH

H

B:

H

H

O

:B

H

H

H

O

:B

H

H

H

O

H

H

O

B:

H

OH

H

O

B:

H

O

H :BProposedMechanism:



OLiNEt2

Et2O,

H

H

OH

OHCHO + +

55-60% 10-15%32%


OOLiNEt2

Et2O, -10°C


H

H

OH

HB:

H

H

OH

H

B:

H

H

O

:B

H

H

H

O

:B

H

H

H

O

H

H

O

B:

H

OH

H

O

B:

H

O




OLiNEt2

Et2O,

H

H

OH

OHCHO + +

55-60% 10-15%32%


OOLiNEt2

Et2O, -10°C


H

H

OH

HB:

H

H

OH

H

B:

H

H

O

:B

H

H

H

O

:B

H

H

H

O

H

H

O

B:

H

OH

H

O

B:

H

O




OLiNEt2

Et2O,

H

H

OH

OHCHO + +

55-60% 10-15%32%


OOLiNEt2

Et2O, -10°C


H

H

OH

HB:

H

H

OH

H

B:

H

H

O

:B

H

H

H

O

:B

H

H

H

O

H

H

O

B:

H

OH

H

O

B:

H

O




OLiNEt2

Et2O,

H

H

OH

OHCHO + +

55-60% 10-15%32%


OOLiNEt2

Et2O, -10°C


H

H

OH

HB:

H

H

OH

H

B:

H

H

O

:B

H

H

H

O

:B

H

H

H

O

H

H

O

B:

H

OH

H

O

B:

H

O


H

Asymmetric Deprotonation of Epoxides

Can Reactivity Be Controlled?

–H –H

RLiAddition

–Li2O

O

HH

O

Li

OLiOLi

OLi

Li

R

R

O

E

OLi OLiOLi

ElectrophileTrapping

ReductiveAlkylation

1,2-HydrideShift

C-H or C=CInsertion

C-HInsertion

Electrocyclic-Ring Opening

Hodgson and Gras, Synthesis, 2002, 12, 1625

Base

Asymmetric ß-Deprotonation of Epoxides

Allylic Alcohols Using Lithium Aminoamide Bases

N

N

LiO

OH

77%79% ee

THF, 0°C

TBSO O TBSO

OH

TBSOO

C16H33

TBSO OH

C16H33

92%90% ee

75%89% ee

Ph

NLi

N

PhH, 0°C30 h

O

N

H

Li

HN

H

O

N

H

Li

HN

H

Favored Disfavored

Asami, et. al. Tetrahedron, 1995, 51, 11725

Singh, et. al. J. Org. Chem, 1996, 61, 6108

TBSO O TBSO

OH

66%97% ee

Li amide

PhH, 4°C

Li amide

PhCH3, 0°C

Proposed Selectivity Model:

Asymmetric ß-Deprotonation of Epoxides

Use of Commercially-Available Ephedrine-Based Aminoalcohols

R O R

R = OBn 91%, 86% eeR = CH2OH 57%, 95% ee

Hodgson, et. al. Tetrahedron: Asymmetry, 1996, 7, 407

OH

Ph

LiHN OLi

O

R = Me 63%, 99% eeR = Bu 67%, 96% eeR = BnOCH2 76%, 89% ee

Ph

LiHN OLi

HO

R

OHHO

R

Murphy, et. al. J. Chem. Soc., Chem. Commun., 1993, 884

Catalytic Asymmetric Examples

Recent Studies Allow Similar Levels of Selectivity

Andersson, et. al. J. Am. Chem. Soc., 1998, 120, 10760

Asami, et. al. Tetrahedron: Asymmetry 1994, 5, 793 Tetrahedron Lett. 1997, 38, 6425

O

OH

N

N

LiN

N

LiH

H

Li amide (20 mol %)

LDA, THF, rt

+ 1 equiv LDA + 6 equiv DBU12 h, 71%, 75% ee

+ 1.8 equiv LDA6 h, 95%, 88% ee

n

NHN

catalyst (5 mol%)

n = 1 91%, 96% een = 2 89%, 96% een = 3 81%, 78% ee

O

nOHLDA (2 equiv)

THF/DBU (95:5)0°C, 24 h

NH H

O

OH

catalyst (20 mol%)

LDA (1.25 equiv)THF, 0°C, 15 h

Li

77%95% ee

Malhotra, Tetrahedron: Asymmetry, 2003, 14, 645

Enantioselective -Deprotonation of Epoxides

Transannular C-H Insertion With Alkyllithium Diamine Complexes

(–)-sparteine (2.5 equiv)

i-PrLi (2.4 equiv)Et2O, -98°C to rt, 20 h

Hodgson, et. al. J. Chem. Soc., Perkin Trans 1, 2001, 2161

O

O

O

OHH

H

H

H

OH

H

H

OH

86%84% ee

77%83% ee

97%77% ee

BocN O

N

OHO

Ot-Bu

(–)- -isosparteine (24 mol %)

i-PrLi (2.4 equiv)Et2O, -98°C, 40 h

NN

NN

N

OLi

Boc

NBoc

O

Li

Hodgson and Lee, Chem. Commun. 1996, 1015

54%, 89% ee

More Transannular Epoxide Rearrangements

Reactivity Differences in Bicyclic Systems

Hodgson and Marriott,Tetrahedron: Asymmetry, 1997, 8, 519

Li amideEt2O

0°C to rt

NN

O

O

HH

HH

Ph N

Li

Ph

chiral baseOH

H

Ph N

Li

PhO

40%, 32% ee 20%, 38% ee

OH

H

+

O

HLiH

OLi

H

HydrideShift

O

LiH

H

OLi

Ha

Hb

HaShift Hb

Shift

(–)-sparteines-BuLi

pentane-78°C to rt

73%, 49% ee 73%, 52% ee

HaHb

Trapping of Lithiated Epoxides

Enantioselective Epoxide Substitution with Various Electrophiles

Hodgson, et. al. Org. Biomol. Chem. 2003, 1, 4293

O

Conditions

s-BuLi (1.25 equiv)(–)-sparteine (1.3 equiv)

Et2O, -90°C, 3 hthen

electrophile (1.5 equiv)-90°C to rt over 5 h

O

TMSO

O

OO

SnR3

OO

O

HO

PhO

Ph

HO

Et

HO

Et

EtO

Et

O

OEt

72%, 74% ee

R = Bu; 72%, 74% eeR = Me; 65%, 78% ee

58%, 81% ee 75%, 77% ee

74%, 76% ee

68%, 77% ee80%, 76% ee

67%, 78% ee

EtCONMe2

PhCHO

EtCHOR3SnCl

PhCONMe2TMSCl

Et2COEtOCOCl

Deprotonation Adjacent to Heteroatoms

A Return to Reaction Pathways

R X

Ha Hb base

- Ha

- Hb

R X

M Hb

R X

Ha M

electrophile

electrophile

R X

E Hbretention

inversion

retention

inversion

R X

Hb E

R X

Ha E

R X

E Ha

R = Ph (usually)X = S, P, Se, etc.

Asymmetric Deprotonation Adjacent to Heteroatoms

• X = O, R = Alkyl

• X = CH=CR'OR'', R = Aryl, Alkyl

• X = N, R = Alkyl, Aryl, Allyl

Deprotonation Adjacent to Oxygen

Alkyl Carbamates

OCbyR

HS HR

1. s-BuLi (–)-sparteine

2. Electrophile

OCbyR

EN

O

OCby =

OCbyMe

E

E % Yield % ee

86 > 96

PbMe3 61 93

CH2CH=CH2 60 42

D

OCbyR

Me

% Yield % ee

60 98

64 92

85 > 95

H3C(CH2)11

R

CbyO

OCby

E

E % Yield % ee

56 > 95

Bu3Sn 70 > 95

Me3Si 70 > 95

CO2Me

Bn2N

Me 72 > 95

FeOCby

PPh2

80%> 95% ee

TBSO OCby

SnBu3

85%> 95% ee

CbyO OCby

CO2Me

80%> 95% ee

Hoppe, et. al. Angew. Chem., Int. Ed. Engl. 1990, 29, 1422 Angew. Chem., Int. Ed. Engl. 1992, 31, 1505 Synthesis 1999, 1573 Org. Lett. 2002, 4, 2189

Asymmetric Deprotonation of Alkyl Carbamates

Intramolecular Reactionss-BuLi

(–)-sparteine

Et2O-78°C to rt

N

O

OCby =

Hoppe, et. al. Synlett 1994, 1034

Ph O N(i-Pr)2

O

Ph

OH

O

N(i-Pr)2

Ph O N(i-Pr)2

OLi

PhO

H OLi

N(i-Pr)2

-78°C to rt

46%96% ee

Tomooka, Shimizu, Inoue, Shibata,l Nakai, Chem. Lett. 1999, 759

CbyO OCby

Li(sparteine)

CbyO OCby

s-BuLi(–)-sparteine

Et2O, -78°C

TMSClor ZnCl2

TBSOTfor BF3•OEt2

H

OCby

> 95% ee

OCby

H

74% ee

Silyl Alkenyl Carbamates

Configurationally Stable Allyllithiums

Hoppe, et. al. Org. Lett. 2004, 6, 783

Ph TMS

OCbxE

TMS

OCbxE

E % Yield % ee

85 95

Bu3Sn 80 95

MeOC(O) 35 72

Me3Si

E % Yield % ee

18 92

Bu3Sn 61 95

Ph3Sn 96 95

Me3Si

t-BuC(O) 66 83

Ph3Sn 83 95

Ph TMS

OCbxE

E % Yield % ee

72 95

t-BuC(O) 94 95

Me2COH 92 95

MeOC(O)

R TMS

OCbxH H

n-BuLi(–)-sparteine

PhCH3, -78°C

R TMS

O

O

Li

(i-Pr)2N

R TMS

OCbxE

OCbx = N(i-Pr)2

O

R = Ph

Ph TMS

OCbxLi

Ph TMS

OCbxR' R'

O

HO R'R'

electrophile

82 90cC6H11OH

Enantioselective Homoaldols

Metal Exchange to Ti Leads to a Highly Diastereoselective Process

R TMS

OCbxH H

n-BuLi(–)-sparteine

PhCH3, -78°C

R TMS

O

O

Li

(i-Pr)2N

R' % Yield % ee

70 95

72 95

cC6H11 69 95

CH3(CH2)2

71 89

TMS

OCbxMe

R'

OH

OCbx = N(i-Pr)2

O

TiCl(NEt2)3 RTMS

Ti(NEt2)3OCbx

R'CHO

R'

OH

R

TMS

OCbx

(CH3)2CH

C6H5

80 95(CH3)3C

R' % Yield % ee

98 91

95 94

cC6H11 93 97

CH3(CH2)2

99 95

TMS

OCbxPh

R'

OH

(CH3)2CH

4-BrC6H4

98 95(CH3)3C

Hoppe, et. al. Org. Lett. 2004, 6, 783

Deprotonation Adjacent to Nitrogen

Alkyl Carbamates Revisited

N

Boc

N


Et2O, -78°C

N

Boc

HR

HS

HS

HR

Li electrophileN

Boc

E

Ot-BuO

E % Yield % ee

88 94

Me3Si 71 94

Bu3Sn 83 96

Me

CO2H 55 88

N

N

Boc

E N

Boc

E

40-50%0-88% ee

15-70%94-98% ee

Beak, et. al. J. Org. Chem. 1997, 62, 7679Coldham, et. al. Org. Lett. 2001, 3, 3799

Beak, et. al. J. Am. Chem. Soc. 1994, 116, 3231

N

Boc

1. CuCN•LiCl

2. alkenyl iodideLi N

Boc R1

R2

R3

Dieter, et. al. J. Am. Chem. Soc. 2001, 123, 5132

89-95%86-90% ee

Benzylic Carbamates

Configurationally Stable Benzyllithiums Possible

% Yield % ee

81 94

Et 78 94

Me


PhX

chiralbase

PhX

M*enantioselective

electrophile

substitution PhX

EMost Benzylic

Deprotonations:

Configurationally

Unstable Anions

PhNAr

chiral base

enantioselectivedeprotonation

PhNAr

M* electrophilesubstitution

PhNAr

EX = NArBoc:

Enantiomeric Anions

Do Not Interconvert

at Low Temp!

BocBoc Boc

MeO

N

Boc

Ph HN

Boc

Ph

R1. n-BuLi (–)-sparteine

2. ROTf3. CAN

R

69 93

Bn 73 96

Allyl

More Benzylic Carbamates

Applications and Electrophiles

Beak, et. al. J. Am. Chem. Soc. 1997, 119, 10537 J. Org. Chem. 1999, 64, 2996

N

Boc

Ph

1. n-BuLi (–)-sparteine

2. Michael AcceptorN

Boc

Ph

E

Ph

N

Ar

BocO

R

R = H: 72%, 94% ee

R = Me: 63%, 94% ee

Ph

N

Ar

Boc

n = 1: 86%, >99:1 dr, 92% ee

n = 2: 82%, >99:1 dr, 92% ee

O

n

Ph

N

Ar

Boc

91%, 92:8 dr, 90% ee

PhNC

CN

Ar = p-MeOC6H4Ar Ar

N

Boc

Ar


PhCH3, -78°C

ClN Ar

Boc

% Yield % ee

72 96

1-Naphthyl 68 92

Ph

Ar

52 92

3-furyl 21 96

3-thienyl


Lithium Amides in Benzylic Deprotonation

Cyclization of Arylamides Leads to Isoindolones

Clayden, et. al. Tetrahedron 2002, 58, 4727 J. Am. Chem. Soc. 2005, 127, 2412

MeO

N

O

Ph

Ph MeO

N

O

Ph

PhLi

-78 to 0°C

MeO

N

OLi

PhPhH

1. NH4Cl, H2O2. HCl, H2O

O

N

O

PhPhH

H

Ph N

Li

88%, 81% ee

NH

CO2HCO2H

(–)-kainic acid

NH

CO2HCO2H

HO2C(–)-isodomoic acid C

Enantioselective N-Allylcarbamate Deprotonation

Beak, et. al. J. Am. Chem. Soc. 1996, 118, 12218 J. Am. Chem. Soc. 2001, 123, 1004

Ph

NAr Boc

Ph H

NLiBocAr

n-BuLi(–)-sparteine electrophile

Ph

NAr Boc

EAr = p-MeOC6H4

% Yield % ee

73 94

Bn 70 96

Me

E

Allyl 72 94

R

NAr Boc

1. n-BuLi (–)-sparteine

2. Carbonyl or Michael Acceptor

R

ArNBoc

HO

R' R''

ArNBoc

77%, 98% ee

Ph

OH

ArNBoc

80%, 86% ee90:10 dr

Ph

N

O

ArNBoc

62%, 96% ee80:20 dr

Me

O

ArNBoc

80%, 92% ee89:11 dr

Ph

O

O

Boc

ArNBoc

80%, 88% ee63:44 dr

Ph

Cy

NC

ArNBoc

86%, 96% ee94:6 dr

Ph

Ph

EtO2C

ArNBoc

73%, >94% ee98:2 dr

Ph

i-Bu

O2N

CNEtO2C

ArNBoc

R

R'

R''

OH

Enantioselective Synthesis by Loss of HX

Chiral Amides Lead to Enantioenriched Alkenes

Duhamel, et. al. Tetrahedron: Asymmetry, 1990, 1, 347

H

H

X OTf

Ph N

Et2O, -70°CH

H

X

X = O 44% ee

X = –O(CH2)2O– 99% ee

Sakai, et. al. Tetrahedron Lett. 1987, 28, 6489

R

Cl

HO2C

N

Li

Ph

THF, -78°C

R

HO2C

R = Me 80% ee

R = t-Bu 82% ee

Me

Cl

N

Li

Ph

THF, -78°C

Me

75% ee

CO2H CO2H

More Enantioselective Loss of HX

Chiral Alkoxides Allow Catalytic Reactions

Duhamel, et. al. J. Org. Chem., 1998, 63, 5541

OO

BrR

Br Ph

HO

NMe2

(10 mol %)

MeOH (4 mol %)KH, THF

-80°C, 72 h

OO

R

Br

H

% Yield % ee

83 90

n-Pr 78 77

t-Bu

R

79 65

p-PhC6H4 81 96

i-Pr

Ph 82 94

79 >98p-MeOC6H4

78 >98p-NO2C6H4

KH

H2

2.5 equiv4 mol %

MeOH

MeOK

10 mol %

Ph

K+ -O

NMe2

Ph

HO

NMe2

OO

BrR

Br

OO

R

Br

H

Enantioselective Lithiation of Aromatics

Generation of Planar Chirality with Lithium Amide Bases

Simpkins, et. al. J. Chem. Soc., Perkin Trans 1, 1997, 401

Ph N

Li

Ph

Fe

PPh2

O

TMSCl, THF-78°C

Fe

PPh2

O

TMS95%

54% ee

Simpkins and Price, Tetrahedron Lett., 1995, 36, 6135

OMe

Cr(CO)3

Ph N

Li

Ph

LiCl, THF-78°C, 15 min

OMe

Cr(CO)3

Li

OMe

Cr(CO)3

OH

PhPhCHO 67%

65% ee

Enantioselective Lithiation of Aromatics

Generation of Planar Chirality with Alkyllithium / Sparteine

Uemura, et. al. Tetrahedron: Asymmetry, 1994, 5, 1427

Fe

O

Fe

O

Snieckus, et. al. J. Am. Chem. Soc., 1996, 118, 685

N(i-Pr)2

1. n-BuLi (–)-sparteine Et2O, -78°C

2. electrophile

E

N(i-Pr)2

% Yield % ee

96 98

Me 91 94

TMS

E

Ph2C(OH) 91 99

85 96

Ph2P 82 90

I

89 85B(OH)2

O

Cr(CO)3

t-BuLiPhCH3, -78°C

Ph2PCl 85%75% ee

Ph

Me2N NMe2

Ph

O

Cr(CO)3

Li

O

Cr(CO)3

PPh2

N

O

O

O

N

O

O

N

O

Documents

sparteine i-PrLi, Et Asymmetric Deprotonation · Cox and Simpkins, "Asymmetric Synthesis Using Homochiral Lithium Amide Bases," Tetrahedron: Asymmetry, 1991, 2 (1), 1-26. 8. Eames,